Norepinephrine reuptake bupropion effects

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

D. Mirtazapine acts at serotonin and adrenergic receptors and does not effect reuptake of neurotransmitters. Venlafaxine is a mixed serotonin-norepinephrine reuptake inhibitor. Bupropion inhibits norepinephrine and dopamine reuptake. 

Bupropion is an aminoketone that exerts its therapeutic effect through the inhibition of norepinephrine and dopamine reuptake. Bupropion s receptor occupancy profile shows an absence of anticholinergic and antihista-minic effects (Cusack et ah, 1994). Bupropion is absorbed rapidly from the gastrointestinal tract, and peak blood levels are achieved within 2 hours for regular release and 3 hours for sustained-release preparations = 10 hours). Bupropion undergoes extensive first-pass metabolism in the liver, yielding three active metabolites hydrobupropion, threohydroxybu-propion, and erythrohydrobupropion. The half-lives of the active metabolites are approximately 20 + hours (Preskorn, 1993). 

Extensive studies on bupropion, including animal models of depression, have demonstrated that the desired inhibition of dopamine and norepinephrine reuptake resides mainly with radafaxine (that is the (S,S)-enantiomer, 2a). Furthermore, these studies confirmed that the (R,R) -enantiomer, 2b, is associated with a number of the known related undesirable side effects. Hence, development of radafaxine hydrochloride was undertaken for the treatment of Major Depressive Disorder (MDD) as a stand-alone New Chemical Entity (NCE). Furthermore, owing to the undesirable side effects associated with the (R,R)-enantiomer 2b, levels of this compound were to be controlled to <0.5% to minimize these effects. 

Bupropion (Wellbutrin, Zyban] Primarily inhibits dopamine reuptake little effect on norepinephrine or serotonin Low sedative, anticholinergic, and cardiovascular side effects also used as an intervention to quit cigarette smoking May cause overstimulation (insomnia, tremor) and induce psychotic symptoms... 

The forced swim test and other assays that are used to identify antidepressant compounds detect compounds with different types of drug action—i.e., serotonin reuptake blockers, norepinephrine reuptake blockers, and atypical antidepressants. A major concern with these types of assays is the identification of false positive compounds. Traditionally, test compounds are evaluated in the forced swim test and in locomotor activity assays to test for stimulant activity. Stimulant compounds are considered false positives in the forced swim test since swimming is considered by some a form of locomotion. However, there are some compounds that increase dopaminergic signaling, such as nomifensine and bupropion, that had antidepressant-like effects in clinical and preclinical tests and demonstrated stimulant activity in some studies [37,38]. Interestingly, stimulant drugs are normally considered false positives in the forced swim test because they are not prescribed for depressed patients however, no controlled studies have been conducted to test this assumption. 

Atypical antidepressants represent a heterogeneous group comprising agents that interfere only weakly or not at all with monoamine reuptake (trazodone, nefazo-done, bupropion, mirtazapine), preferentially block reuptake of norepinephrine (re-boxetine), or act as dual inhibitors of 5-HT and norepinephrine reuptake (venlafaxine, milnacipran, duloxetine). Venlafaxine appears to be as effective as tricyclic antidepressants in severe depression. 

Tricyclics modify peripheral sympathetic effects in two ways through blockade of norepinephrine reuptake at neuroeffector junctions and through alpha adrenoceptor blockade. Sedation and atropine-like side effects are common with tricyclics, especially amitriptyline. In contrast to sedative-hypnotics, tricyclics lower the threshold to seizures. The answer is (B). Selective serotonin reuptake inhibitors cause sexual dysfunction in some patients, with changes in libido, erectile dysfunction, and anorgasmia. Tricyclic antidepressants may also decrease libido or prevent ejaculation. Of the heterocyclic antidepressants bupropion is the least likely to affect sexual performance. The drug is also used in withdrawal from nicotine dependence. The answer is (B). 

C. Selective norepinephrine reuptake inhibitors. Few studies have been done with selective norephinephrine inhibitors. Bupropion have shown effect but the adverse event profile does not place these compounds as a first line treatment option. 

Bupropion is a monocyclic antidepressant that inhibits the reuptake of norepinephrine and dopamine. Bupropion is effective for relieving symptoms of ADHD in children but is... 

Bupropion is another alternative pharmacological approach to tobacco abstinence. It is an antidepressant drug that blocks reuptake of norepinephrine and dopamine, and also blocks nicotinic receptors in the low to intermediate micromolar range (Fryer and Lukas 1999). Thus, the effects of bupropion on nicotine addiction may be through dual effects on dopaminergic and nicotinic systems. Further, it has been an effective treatment in controlled studies, both alone and in combination with the nicotine patch. Bupropion alone or in combination with a nicotine patch was more effective than placebo or the nicotine patch alone. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Nortriptyline (Pamelor). A recent study suggested that the tricyclic antidepressant nortriptyline, like bupropion, is effective in the treatment of smoking cessation. Nortriptyline does not have any significant effect on dopamine reuptake activity, but it does increase norepinephrine availability. Like bupropion, nortriptyline may therefore reduce the physical symptoms of nicotine withdrawal. Because nortriptyline carries the danger of lethality in overdose and has the unfavorable side effect profile of the tricyclics, we do not recommend its use for smoking cessation. However, it does raise the question as to whether other newer antidepressants that increase norepinephrine activity (e.g., venlafaxine, mirtazapine, duloxetine) may also prove to be effective treatments for nicotine withdrawal. 

Bupropion belongs to the chemical class of aminoketones. It is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist. Initially developed and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. If given to lactating women it can trigger convulsions in the newborn. 

The actions of bupropion remain poorly understood. Bupropion and its major metabolite hydroxybupropion are modest-to-moderate inhibitors of norepinephrine and dopamine reuptake in animal studies. However, these effects seem less than are typically associated with antidepressant benefit. A more significant effect of bupropion is presynaptic release of catecholamines. In animal studies, bupropion appears to substantially increase the presynaptic availability of norepinephrine and dopamine to a lesser extent. Bupropion has virtually no direct effects on the serotonin system. 

Bupropion (amfebutamon) shows structural similarity with amphetamine (p.329) and inhibits neuronal reuptake of dopamine and norepinephrine. It is supposed to aid smokers in kicking the habit, possibly because it evokes CNS effects resembling those of nicotine. The high relapse rate after termination of the drug and substantial side effects put its therapeutic value in doubt. 

Another efficient modality for smoking cessation is bupropion.The antidepressant activity of bupropion is achieved through its effects on the levels of dopamine and norepinephrine in the brain (the effects of bupropion are mediated by blocking the reuptake of both dopamine and norepinephrine ). These effects are thought to underlie its positive results in clinical trials of patients with tobacco dependence (bupropion about doubles long-term abstinence rates compared with placebo). Increased brain levels of dopamine and norepinephrine would be expected to counteract the deficiency of these neurotransmitters during nicotine withdrawal and thereby aid in smoking cessation. 

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